COL4A1

Final classification

VUS

COL4A1 c.343G>A · p.Gly115Ser

COL4A1

NM_001845.5:c.343G>A (p.Gly115Ser) is a missense variant in COL4A1 affecting a glycine residue in the collagen triple-helical Gly-X-Y repeat domain.

Gene

COL4A1

Transcript

NM_001845.5

HGVS · transcript:coding

NM_001845.5:c.343G>A

Consequence

N/A

GRCh38

chr13:110212461 C>T

GRCh37

chr13:110864808 C>T

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting, PP3 supporting; combination = 1 moderate + 2 supporting, which maps to VUS. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting, PP3 supporting; combination = 1 moderate + 2 supporting, which maps to VUS.

Classification rationale

PM1PM2PP3 VUS

COL4A1 c.343G>A

NM_001845.5:c.343G>A (p.Gly115Ser) is a missense variant in COL4A1 affecting a glycine residue in the collagen triple-helical Gly-X-Y repeat domain. The variant is extremely rare in population databases: gnomAD v2.1 allele frequency is 0.00177% (5/282,856 alleles) and gnomAD v4.1 allele frequency is 0.00192% (31/1,613,960 alleles), both well below the 0.1% PM2 threshold. It is absent from gnomAD-Canada.¹ Gly115 lies within the collagen triple-helical domain, a critical functional domain where glycine substitutions are a well-established pathogenic mechanism across collagen genes and specifically in COL4A1-related disorders (PMID:25719457). This supports application of PM1 at moderate strength. In silico predictors support a deleterious effect: REVEL score 0.963 (highly pathogenic-leaning) and BayesDel score 0.571 (damaging), meeting PP3 at supporting strength.² In ClinVar (ID 2158622), this variant has been reported as Uncertain significance by 5 clinical laboratories and as Likely pathogenic by 1 clinical laboratory (Labcorp Genetics). No expert panel review is available.³ Exploratory evidence recovery suggests potential functional evidence of impaired collagen IV secretion (PMID:15905400) and a possible de novo observation, but these could not be independently verified from available abstracts and require human review of full-text publications. Applying generic ACMG/AMP 2015 criteria: PM1 (moderate) + PM2 (supporting) + PP3 (supporting) = 1 moderate + 2 supporting, which does not reach the Likely Pathogenic threshold (requires ≥2 moderate OR ≥4 supporting OR 1 strong + ≥2 supporting). The classification is Variant of Uncertain Significance. Additional evidence (PS3 functional confirmation, PM6 de novo verification) could upgrade this to Likely Pathogenic.⁴

PM1 + PM2 + PP3 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 revelbayesdel

3 clinvar ↗

4 generic_acmg_combination_rules

Gene diagram · NM_001845.5 · variants mapped to exon structure

COL4A1 NM_001845.5

Fetching transcript structure from UCSC…

Applied criteria · 3 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

Population frequency

Overall AF

31 / 1,613,960

0.0019%

Highest · African/African American

0.0027%

Homozygotes

grpmax FAF

0.0016%

Allele frequency by ancestry — gnomAD v4.1

observed in 3 of 9 groups

Ancestry	Allele count	Frequency	Homozygotes
African/African American	2 / 74,868	0.0027%	0
European (non-Finnish)	27 / 1,180,042	0.0023%	0
Admixed American	1 / 59,992	0.0017%	0
European (Finnish)	0 / 64,036	—	—
Amish	0 / 912	—	—
East Asian	0 / 44,896	—	—
Middle Eastern	0 / 6,048	—	—
South Asian	0 / 91,080	—	—
Ashkenazi Jewish	0 / 29,604	—	—

“

This variant is present in gnomAD v4.1 (AF= 1.92074e-05; MAF= 0.00192%, 31/1613960 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.67137e-05; MAF= 0.00267%, 2/74868 alleles, homozygotes = 0); grpmax FAF= 1.567e-05.

Overall AF

5 / 282,856

0.0018%

Highest · European (non-Finnish)

0.0031%

Homozygotes

grpmax FAF

0.0007%

Allele frequency by ancestry — gnomAD v2.1

observed in 2 of 8 groups

Ancestry	Allele count	Frequency	Homozygotes
European (non-Finnish)	4 / 129,168	0.0031%	0
Admixed American	1 / 35,440	0.0028%	0
African/African American	0 / 24,964	—	—
Ashkenazi Jewish	0 / 10,368	—	—
East Asian	0 / 19,952	—	—
European (Finnish)	0 / 25,124	—	—
Remaining individuals	0 / 7,224	—	—
South Asian	0 / 30,616	—	—

“

This variant is present in gnomAD v2.1 (AF= 1.76768e-05; MAF= 0.00177%, 5/282856 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.09674e-05; MAF= 0.00310%, 4/129168 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.

“

This variant is absent from gnomAD-Canada.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 2158622)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.963. BayesDel score = 0.571004.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV65433356, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · 10 PMIDs triaged · 7 high-priority

10papers screened

Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.

17078022 ↗ functional

Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans.

Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the proalpha1(I) and proalpha2(I) chains, respectively) that result in OI. Quantitative

BS3PP5PS3PS4

19344236 ↗ functional

Collagen structure and stability.

Collagen is the most abundant protein in animals. This fibrous, structural protein comprises a right-handed bundle of three parallel, left-handed polyproline II-type helices. Much progress has been made in elucidating the structure of collagen triple helices and the physicochemical basis for their stability. New evidence demonstrates that stereoelectronic effects and preorganization play a key rol

BS3PP5PS3PS4

25741868 ↗ functional

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic

BS3PP5PS3PS4

8218237 ↗ functional

Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence.

Glycine is found as every third residue along the entire length of triple helices in fibrillar collagens, but the triple-helix regions of nonfibrillar collagens and other proteins usually contain one or more interruptions in this repeating pattern. A set of four peptides was designed to model the effect of interruptions in the (Gly-X-Y)n repeating pattern on triple-helix formation, stability, and

BS3PP5PS3PS4

20301386 ↗ case observation

Untitled reference

PP5PS4

20301768 ↗ case observation

Untitled reference

PP5PS4

9016532 ↗ case observation

The human type I collagen mutation database.

Type I collagen is the most abundant and ubiquitously distributed of the collagen family of proteins. It is a heterotrimer comprising two alpha1(I) chains and one alpha2(I) chain which are encoded by the unlinked loci COL1A1 and COL1A2 respectively. Mutations at these loci result primarily in the connective tissue disorders osteogenesis imperfecta and Ehlers-Danlos syndrome types VIIA and VIIB. Tw

PP5PS4

25355838 ↗ background review

Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association.

PP5PS4

28492532 ↗ background review

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

PP5PS4

7695699 ↗ background review

Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution.

PP5PS4

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots