NM_138691.3(TMC1):c.1939T>C (p.Ser647Pro) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 25, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001782704.6

Allele description [Variation Report for NM_138691.3(TMC1):c.1939T>C (p.Ser647Pro)]

NM_138691.3(TMC1):c.1939T>C (p.Ser647Pro)

Gene:

TMC1:transmembrane channel like 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q21.13

Genomic location:

Preferred name:

NM_138691.3(TMC1):c.1939T>C (p.Ser647Pro)

HGVS:

NC_000009.12:g.72821017T>C
NG_008213.1:g.304217T>C
NM_138691.3:c.1939T>CMANE SELECT
NP_619636.2:p.Ser647Pro
NP_619636.2:p.Ser647Pro
NC_000009.11:g.75435933T>C
NM_138691.2:c.1939T>C

Protein change:

S647P

Links:

dbSNP: rs138527651

NCBI 1000 Genomes Browser:

rs138527651

Molecular consequence:

NM_138691.3:c.1939T>C - 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
SCV002018978	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 29, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003805702	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Feb 14, 2023)	germline	clinical testing	Citation Link,
SCV004294329	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 25, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21917145, 31814694, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002018978

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 29, 2019)

germline

clinical testing

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

SCV003805702

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Feb 14, 2023)

germline

clinical testing

Citation Link,

SCV004294329

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 25, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

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.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families.

Brownstein Z, Friedman LM, Shahin H, Oron-Karni V, Kol N, Abu Rayyan A, Parzefall T, Lev D, Shalev S, Frydman M, Davidov B, Shohat M, Rahile M, Lieberman S, Levy-Lahad E, Lee MK, Shomron N, King MC, Walsh T, Kanaan M, Avraham KB.

Genome Biol. 2011 Sep 14;12(9):R89. doi: 10.1186/gb-2011-12-9-r89.

PubMed [citation]

PMID:: 21917145
PMCID:: PMC3308052

See all PubMed Citations (4)

Details of each submission

From Revvity Omics, Revvity, SCV002018978.3

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

#	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 GeneDx, SCV003805702.1

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

Description

S647P has been described as a founder mutation, contributing to nearly a third of genetic hearing loss among the Moroccan Jewish population (Brownstein et al., 2011; Ehrenberg et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22269275, 21917145, 24933710, 31814694, 31589614, 34795337, 24156272, Aboagye2023[paper], 27344577)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004294329.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 647 of the TMC1 protein (p.Ser647Pro). This variant is present in population databases (rs138527651, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 21917145, 31814694). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228408). 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) performed at Invitae indicates that this missense variant is expected to disrupt TMC1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine