The p.Asp572Asn in TMC1 has been previously reported in 3 probands with nonsyndr omic bilateral sensorineural hearing loss, and segregated with disease in a domi nant pattern in >10 affected family members (Kurima 2002, Hilgert 2009, Makishim a 2004, Wei 2014). The hearing loss was reported to be progressive with a postli ngual onset. The variant was identified in one unaffected individual from one fa mily, indicating that the penetrance may not be complete; however the age of thi s individual was also not reported (Hilgert 2009). This variant was absent from large population databases. A variant affecting the same amino acid (p.Asp572His ) has also been reported in an individual with hearing loss and segregated in 7 affected family members including 2 obligate carriers (Kitajiri 2007), further s upporting that missense variants at this position are not tolerated. Unlike loss of function variants in TMC1, which cause recessive hearing loss, these studies indicate that the p.Asp572Asn and p.Asp572His missense variants cause dominant hearing loss. In summary, the p.Asp572Asn variant meets our criteria to be class ified as pathogenic for autosomal dominant sensorineural hearing loss (http://ww w.partners.org/personalizedmedicine/LMM) based upon segregation studies in affec ted families and its absence in the general population.
ClinVar Genomic variation as it relates to human health
NM_138691.3(TMC1):c.1714G>A (p.Asp572Asn)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_138691.3(TMC1):c.1714G>A (p.Asp572Asn)
Variation ID: 4102 Accession: VCV000004102.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q21.13 9: 72816161 (GRCh38) [ NCBI UCSC ] 9: 75431077 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Mar 18, 2023 Mar 31, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_138691.3:c.1714G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619636.2:p.Asp572Asn missense NC_000009.12:g.72816161G>A NC_000009.11:g.75431077G>A NG_008213.1:g.299361G>A Q8TDI8:p.Asp572Asn - Protein change
- D572N
- Other names
- -
- Canonical SPDI
- NC_000009.12:72816160:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TMC1 | - | - |
GRCh38 GRCh37 |
737 | 780 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Likely pathogenic (3) |
criteria provided, single submitter
|
Sep 28, 2016 | RCV000004318.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 5, 2015 | RCV000217542.13 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 31, 2022 | RCV001810830.14 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Sep 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nonsyndromic hearing loss 36
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Accession: SCV000891297.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jun 05, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Rare genetic deafness
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271465.3
First in ClinVar: May 29, 2016 Last updated: Aug 26, 2019 |
Comment:
The p.Asp572Asn in TMC1 has been previously reported in 3 probands with nonsyndr omic bilateral sensorineural hearing loss, and segregated with disease in a domi … (more)
The p.Asp572Asn in TMC1 has been previously reported in 3 probands with nonsyndr omic bilateral sensorineural hearing loss, and segregated with disease in a domi nant pattern in >10 affected family members (Kurima 2002, Hilgert 2009, Makishim a 2004, Wei 2014). The hearing loss was reported to be progressive with a postli ngual onset. The variant was identified in one unaffected individual from one fa mily, indicating that the penetrance may not be complete; however the age of thi s individual was also not reported (Hilgert 2009). This variant was absent from large population databases. A variant affecting the same amino acid (p.Asp572His ) has also been reported in an individual with hearing loss and segregated in 7 affected family members including 2 obligate carriers (Kitajiri 2007), further s upporting that missense variants at this position are not tolerated. Unlike loss of function variants in TMC1, which cause recessive hearing loss, these studies indicate that the p.Asp572Asn and p.Asp572His missense variants cause dominant hearing loss. In summary, the p.Asp572Asn variant meets our criteria to be class ified as pathogenic for autosomal dominant sensorineural hearing loss (http://ww w.partners.org/personalizedmedicine/LMM) based upon segregation studies in affec ted families and its absence in the general population. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 28, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473661.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The TMC1 c.1714G>A; p.Asp572Asn variant (rs121908072) is reported in the literature segregating with disease in several families affected with autosomal dominant hearing loss (Hilgert 2009, … (more)
The TMC1 c.1714G>A; p.Asp572Asn variant (rs121908072) is reported in the literature segregating with disease in several families affected with autosomal dominant hearing loss (Hilgert 2009, Kurima 2002, Wang 2018, Wei 2014). This variant is reported in ClinVar (Variation ID: 4102), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1714G>C; p.Asp572His) has been reported in a large family affected with autosomal dominant hearing loss (Kitajiri 2007). Based on available information, this variant is considered to be pathogenic. References: Hilgert N et al. Amino acid 572 in TMC1: hot spot or critical functional residue for dominant mutations causing hearing impairment. J Hum Genet. 2009;54(3):188-190. Kitajiri S et al. A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1. Clin Genet. 2007;71(2):148-152. Kurima et al. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet. 2002 Mar;30(3):277-84. Wang et al. Identification of four TMC1 variations in different Chinese families with hereditary hearing loss. Mol Genet Genomic Med. 2018 Apr 14. Wei Q et al. Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss. J Transl Med. 2014;12:311. Published 2014 Nov 12. (less)
|
|
|
Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002499803.2
First in ClinVar: Apr 23, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: severe disruption of LHFPL5 binding (Yu et al., 2020); Not observed at significant frequency in large population cohorts … (more)
Published functional studies demonstrate a damaging effect: severe disruption of LHFPL5 binding (Yu et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); 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: 17250663, 15354000, 25388789, 26226225, 26079994, 29654653, 31854501, 31541171, 19180119, 11850618, 33168709, 27535533) (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal dominant nonsyndromic hearing loss 36
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760240.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
|
|
Pathogenic
(Mar 01, 2009)
|
no assertion criteria provided
Method: literature only
|
DEAFNESS, AUTOSOMAL DOMINANT 36
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024489.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In a large North American family with autosomal dominant nonsyndromic sensorineural hearing loss that was arbitrarily designated DFNA36 (606705), Kurima et al. (2002) found a … (more)
In a large North American family with autosomal dominant nonsyndromic sensorineural hearing loss that was arbitrarily designated DFNA36 (606705), Kurima et al. (2002) found a 1714G-A transition in the TMC1 gene resulting in an asp572-to-asn amino acid substitution (D572N). Sensorineural hearing loss began at 5 to 10 years of age and rapidly progressed to profound deafness within 10 to 15 years. These was no evidence of vestibular deficits. No polymorphisms at this codon were found in 902 control chromosomes. Hilgert et al. (2009) identified the D572N mutation in another North American Caucasian family with autosomal dominant hearing loss. Comparison of haplotypes with the family reported by Kurima et al. (2002) excluded a founder effect. One asymptomatic individual in the family reported by Hilgert et al. (2009) carried the disease haplotype, indicating reduced penetrance. Yu et al. (2020) examined physical and functional interactions between proteins encoded by TMC1 and LHFPL5 (609427), a gene whose variants are associated with autosomal recessive deafness-67 (DFNB67; 610265) and found that TMC1 expression is stabilized by LHFPL5 binding both in heterologous expression systems and in hair cells. The D572N variant in TMC1 disrupted the interaction between TMC1 and LHFPL5, resulting in destabilized TMC1 expression. (less)
|
Comment:
Comment:
The TMC1 c.1714G>A; p.Asp572Asn variant (rs121908072) is reported in the literature segregating with disease in several families affected with autosomal dominant hearing loss (Hilgert 2009, Kurima 2002, Wang 2018, Wei 2014). This variant is reported in ClinVar (Variation ID: 4102), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1714G>C; p.Asp572His) has been reported in a large family affected with autosomal dominant hearing loss (Kitajiri 2007). Based on available information, this variant is considered to be pathogenic. References: Hilgert N et al. Amino acid 572 in TMC1: hot spot or critical functional residue for dominant mutations causing hearing impairment. J Hum Genet. 2009;54(3):188-190. Kitajiri S et al. A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1. Clin Genet. 2007;71(2):148-152. Kurima et al. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet. 2002 Mar;30(3):277-84. Wang et al. Identification of four TMC1 variations in different Chinese families with hereditary hearing loss. Mol Genet Genomic Med. 2018 Apr 14. Wei Q et al. Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss. J Transl Med. 2014;12:311. Published 2014 Nov 12.
Comment:
Published functional studies demonstrate a damaging effect: severe disruption of LHFPL5 binding (Yu et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); 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: 17250663, 15354000, 25388789, 26226225, 26079994, 29654653, 31854501, 31541171, 19180119, 11850618, 33168709, 27535533)
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The p.Asp572Asn in TMC1 has been previously reported in 3 probands with nonsyndr omic bilateral sensorineural hearing loss, and segregated with disease in a domi nant pattern in >10 affected family members (Kurima 2002, Hilgert 2009, Makishim a 2004, Wei 2014). The hearing loss was reported to be progressive with a postli ngual onset. The variant was identified in one unaffected individual from one fa mily, indicating that the penetrance may not be complete; however the age of thi s individual was also not reported (Hilgert 2009). This variant was absent from large population databases. A variant affecting the same amino acid (p.Asp572His ) has also been reported in an individual with hearing loss and segregated in 7 affected family members including 2 obligate carriers (Kitajiri 2007), further s upporting that missense variants at this position are not tolerated. Unlike loss of function variants in TMC1, which cause recessive hearing loss, these studies indicate that the p.Asp572Asn and p.Asp572His missense variants cause dominant hearing loss. In summary, the p.Asp572Asn variant meets our criteria to be class ified as pathogenic for autosomal dominant sensorineural hearing loss (http://ww w.partners.org/personalizedmedicine/LMM) based upon segregation studies in affec ted families and its absence in the general population.
Comment:
The TMC1 c.1714G>A; p.Asp572Asn variant (rs121908072) is reported in the literature segregating with disease in several families affected with autosomal dominant hearing loss (Hilgert 2009, Kurima 2002, Wang 2018, Wei 2014). This variant is reported in ClinVar (Variation ID: 4102), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1714G>C; p.Asp572His) has been reported in a large family affected with autosomal dominant hearing loss (Kitajiri 2007). Based on available information, this variant is considered to be pathogenic. References: Hilgert N et al. Amino acid 572 in TMC1: hot spot or critical functional residue for dominant mutations causing hearing impairment. J Hum Genet. 2009;54(3):188-190. Kitajiri S et al. A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1. Clin Genet. 2007;71(2):148-152. Kurima et al. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet. 2002 Mar;30(3):277-84. Wang et al. Identification of four TMC1 variations in different Chinese families with hereditary hearing loss. Mol Genet Genomic Med. 2018 Apr 14. Wei Q et al. Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss. J Transl Med. 2014;12:311. Published 2014 Nov 12.
Comment:
Published functional studies demonstrate a damaging effect: severe disruption of LHFPL5 binding (Yu et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); 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: 17250663, 15354000, 25388789, 26226225, 26079994, 29654653, 31854501, 31541171, 19180119, 11850618, 33168709, 27535533)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding. | Yu X | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 33168709 |
| Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss. | Wei Q | Journal of translational medicine | 2014 | PMID: 25388789 |
| Amino acid 572 in TMC1: hot spot or critical functional residue for dominant mutations causing hearing impairment. | Hilgert N | Journal of human genetics | 2009 | PMID: 19180119 |
| A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1. | Kitajiri S | Clinical genetics | 2007 | PMID: 17250663 |
| Early onset and rapid progression of dominant nonsyndromic DFNA36 hearing loss. | Makishima T | Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology | 2004 | PMID: 15354000 |
| Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. | Kurima K | Nature genetics | 2002 | PMID: 11850618 |
Text-mined citations for rs121908072 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.