NM_153676.4(USH1C):c.1823C>G (p.Pro608Arg) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 11, 2023
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:: RCV000755427.14

Allele description

NM_153676.4(USH1C):c.1823C>G (p.Pro608Arg)

Gene:

USH1C:USH1 protein network component harmonin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.1

Genomic location:

Preferred name:

NM_153676.4(USH1C):c.1823C>G (p.Pro608Arg)

Other names:

R608P

HGVS:

NC_000011.10:g.17509546G>C
NG_011883.2:g.39871C>G
NM_001297764.2:c.1228-7566C>G
NM_005709.4:c.1285-7566C>G
NM_153676.4:c.1823C>GMANE SELECT
NP_710142.1:p.Pro608Arg
NC_000011.9:g.17531093G>C
NG_011883.1:g.39871C>G
NM_153676.3:c.1823C>G
c.1823C>G

Protein change:

P608R; ARG608PRO

Links:

OMIM: 605242.0009; dbSNP: rs41282932

NCBI 1000 Genomes Browser:

rs41282932

Molecular consequence:

NM_001297764.2:c.1228-7566C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_005709.4:c.1285-7566C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_153676.4:c.1823C>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000605534	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (May 25, 2018)	germline	clinical testing	Citation Link,
SCV001873907	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Aug 24, 2021)	germline	clinical testing	Citation Link,
SCV003255845	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Oct 11, 2023)	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

SCV000605534

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(May 25, 2018)

germline

clinical testing

Citation Link,

SCV001873907

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Aug 24, 2021)

germline

clinical testing

Citation Link,

SCV003255845

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Oct 11, 2023)

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000605534.2

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

Description

The p.Pro608Arg variant (rs41282932) has been identified in a homozygous state in a single induvial with non-syndromic hearing loss (Ouyang 2002). However it has been identified in several other cases with an alternate molecular basis for hearing loss, suggesting that it is not a causative variant (Cremers 2007, and Vona 2014). The p.Pro608Arg variant has also been reported to ClinVar (Variation ID: 5148). This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.06 percent (identified on 8 out of 12,984 chromosomes) and is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.05 percent (identified on 124 out of 267,276 chromosomes). The proline at position 608 is weakly conserved (considering 12 species) (Alamut v.2.8.1) and computational analyses of the effects of the p.Pro608Arg variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Pro608Arg variant with certainty.

#	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, SCV001873907.1

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

Description

Observed as a heterozygous variant in patients with hearing loss who harbored variants in other hearing loss-related genes (Cremers FP et al., 2007; Vona B et al., 2014; Nonose RW et al., 2018; Roman-Naranjo P et al., 2021); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 16963483, 12136232, 34391192, 30245029, 29739340, 24875298)

#	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, SCV003255845.2

#	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

Last Updated: Sep 16, 2024

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