NM_000091.5(COL4A3):c.361G>A (p.Gly121Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 4, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001855319.5

Allele description [Variation Report for NM_000091.5(COL4A3):c.361G>A (p.Gly121Ser)]

NM_000091.5(COL4A3):c.361G>A (p.Gly121Ser)

Genes:

MFF-DT:MFF divergent transcript [Gene - HGNC]
COL4A3:collagen type IV alpha 3 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q36.3

Genomic location:

Preferred name:

NM_000091.5(COL4A3):c.361G>A (p.Gly121Ser)

HGVS:

NC_000002.12:g.227245990G>A
NG_011591.1:g.86426G>A
NM_000091.5:c.361G>AMANE SELECT
NP_000082.2:p.Gly121Ser
NP_000082.2:p.Gly121Ser
LRG_230t1:c.361G>A
LRG_230:g.86426G>A
LRG_230p1:p.Gly121Ser
NC_000002.11:g.228110706G>A
NM_000091.4:c.361G>A
p.Gly121Ser

Protein change:

G121S

Links:

dbSNP: rs778886174

NCBI 1000 Genomes Browser:

rs778886174

Molecular consequence:

NM_000091.5:c.361G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002158333	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 4, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33369211, 28492532
SCV004564188	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely pathogenic (May 3, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002158333

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 4, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004564188

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Likely pathogenic
(May 3, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Deciphering the pathogenesis of the COL4-related hematuric nephritis: A genotype/phenotype study.

Uliana V, Sebastio P, Riva M, Carli D, Ruberto C, Bianchi L, Graziano C, Capelli I, Faletra F, Pillon R, Mattina T, Sensi A, Bonatti F, Percesepe A.

Mol Genet Genomic Med. 2021 Feb;9(2):e1576. doi: 10.1002/mgg3.1576. Epub 2020 Dec 24.

PubMed [citation]

PMID:: 33369211
PMCID:: PMC8077073

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

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002158333.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 121 of the COL4A3 protein (p.Gly121Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Alport syndrome (PMID: 33369211). ClinVar contains an entry for this variant (Variation ID: 522453). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004564188.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The COL4A3 c.361G>A; p.Gly121Ser variant (rs778886174) is reported in the literature in two compound heterozygous individuals with autosomal recessive Alport syndrome (Uliana 2021). This variant is also reported in ClinVar (Variation ID: 522453) and is found in the general population with an overall allele frequency of 0.003% (8/280812 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.908). Additionally, this glycine occurs in a Gly-X-Y repeat region in a collagen triple helix region, a critical functional domain (Savige 2021). Based on the available information, this variant is considered to be likely pathogenic. References: Savige J et al. Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria. Eur J Hum Genet. 2021 Aug;29(8):1186-1197. PMID: 33854215. Uliana V et al. Deciphering the pathogenesis of the COL4-related hematuric nephritis: A genotype/phenotype study. Mol Genet Genomic Med. 2021 Feb;9(2):e1576. PMID: 33369211.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

ClinVar

Relating variation to medicine