NM_004086.3(COCH):c.1313G>A (p.Arg438His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 27, 2021
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:: RCV000841244.6

Allele description [Variation Report for NM_004086.3(COCH):c.1313G>A (p.Arg438His)]

NM_004086.3(COCH):c.1313G>A (p.Arg438His)

Genes:

COCH:cochlin [Gene - OMIM - HGNC]
LOC100506071:uncharacterized LOC100506071 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

14q12

Genomic location:

Preferred name:

NM_004086.3(COCH):c.1313G>A (p.Arg438His)

HGVS:

NC_000014.9:g.30886148G>A
NG_008211.2:g.16614G>A
NM_001135058.2:c.1313G>A
NM_001347720.2:c.1508G>A
NM_004086.3:c.1313G>AMANE SELECT
NP_001128530.1:p.Arg438His
NP_001334649.1:p.Arg503His
NP_004077.1:p.Arg438His
NC_000014.8:g.31355354G>A
NC_000014.8:g.31355354G>A
NM_004086.2:c.1313G>A
NR_038356.1:n.717C>T

Protein change:

R438H

Links:

dbSNP: rs746680829

NCBI 1000 Genomes Browser:

rs746680829

Molecular consequence:

NM_001135058.2:c.1313G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001347720.2:c.1508G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004086.3:c.1313G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_038356.1:n.717C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000983202	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Dec 19, 2019)	germline	clinical testing	Citation Link,
SCV002184268	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 27, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000983202

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Dec 19, 2019)

germline

clinical testing

Citation Link,

SCV002184268

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 27, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

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 GeneDx, SCV000983202.2

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

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

From Invitae, SCV002184268.3

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

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 681375). This variant has not been reported in the literature in individuals affected with COCH-related conditions. This variant is present in population databases (rs746680829, ExAC 0.03%). This sequence change replaces arginine with histidine at codon 438 of the COCH protein (p.Arg438His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.

#	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: Feb 28, 2024

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