VCV000229240.34 - ClinVar

NM_004568.6(SERPINB6):c.314C>A (p.Ser105Tyr)

Germline

Classification

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.

(7)

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.

Conflicting classifications of pathogenicity
Uncertain significance(6); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004568.6(SERPINB6):c.314C>A (p.Ser105Tyr)

Variation ID: 229240 Accession: VCV000229240.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p25.2 6: 2954708 (GRCh38) [ NCBI UCSC ] 6: 2954942 (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 9, 2018	Oct 20, 2024	Apr 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004568.6:c.314C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004559.4:p.Ser105Tyr	missense
NM_001195291.3:c.326C>A	NP_001182220.2:p.Ser109Tyr	missense
NM_001271822.2:c.356C>A	NP_001258751.1:p.Ser119Tyr	missense
NM_001271823.2:c.371C>A	NP_001258752.1:p.Ser124Tyr	missense
NM_001271824.2:c.314C>A	NP_001258753.1:p.Ser105Tyr	missense
NM_001271825.2:c.314C>A	NP_001258754.1:p.Ser105Tyr	missense
NM_001297699.2:c.314C>A	NP_001284628.1:p.Ser105Tyr	missense
NM_001297700.2:c.314C>A	NP_001284629.1:p.Ser105Tyr	missense
NM_001374515.1:c.326C>A	NP_001361444.1:p.Ser109Tyr	missense
NM_001374516.1:c.314C>A	NP_001361445.1:p.Ser105Tyr	missense
NM_001374517.1:c.182C>A	NP_001361446.1:p.Ser61Tyr	missense
NR_164657.1:n.359C>A		non-coding transcript variant
NC_000006.12:g.2954708G>T
NC_000006.11:g.2954942G>T
NG_027692.1:g.22458C>A

... more HGVS ... less HGVS

Protein change

S109Y, S105Y, S119Y, S124Y, S61Y

Other names

Canonical SPDI

NC_000006.12:2954707:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00060 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00077

1000 Genomes Project 30x 0.00078

The Genome Aggregation Database (gnomAD), exomes 0.00046

Exome Aggregation Consortium (ExAC) 0.00049

The Genome Aggregation Database (gnomAD) 0.00051

Trans-Omics for Precision Medicine (TOPMed) 0.00053

1000 Genomes Project 0.00060

Links

ClinGen: CA3617574 dbSNP: rs148530934 VarSome

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
Gene	OMIM	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.
SERPINB6		-	-	GRCh38 GRCh37	159	216

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.
not specified	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 29, 2024	RCV000223127.8
Usher syndrome	Uncertain significance (1)	criteria provided, single submitter	Apr 12, 2021	RCV001375306.4
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Mar 22, 2023	RCV001547089.25

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 benign (Aug 25, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001766714.1 First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021
Uncertain significance (Apr 12, 2021)	criteria provided, single submitter (ClinGen HL ACMG Specifications v1) Method: clinical testing	Usher syndrome Affected status: yes Allele origin: germline	Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center Accession: SCV001571928.2 First in ClinVar: Apr 29, 2021 Last updated: Apr 29, 2021	Comment: PM2_Supporting, PP3_Supporting, BP5_Supporting Testing laboratory: CeGaT Praxis fuer Humangenetik Tuebingen
Uncertain significance (Oct 17, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002182846.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Comment: This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 105 of the SERPINB6 protein (p.Ser105Tyr). … (more) This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 105 of the SERPINB6 protein (p.Ser105Tyr). This variant is present in population databases (rs148530934, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SERPINB6-related conditions. ClinVar contains an entry for this variant (Variation ID: 229240). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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. (less)
Uncertain significance (Apr 29, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003756915.3 First in ClinVar: Feb 07, 2023 Last updated: Aug 11, 2024	Comment: The c.314C>A (p.S105Y) alteration is located in exon 4 (coding exon 3) of the SERPINB6 gene. This alteration results from a C to A substitution … (more) The c.314C>A (p.S105Y) alteration is located in exon 4 (coding exon 3) of the SERPINB6 gene. This alteration results from a C to A substitution at nucleotide position 314, causing the serine (S) at amino acid position 105 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Feb 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002497378.18 First in ClinVar: Apr 08, 2022 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (Mar 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004227180.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: BS1_supporting Number of individuals with the variant: 1
Uncertain significance (Apr 13, 2017)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000272422.3 First in ClinVar: May 29, 2016 Last updated: Apr 09, 2018	Comment: The p.Ser105Tyr variant in SERPINB6 has been previously reported by our laborato ry in the heterozygous state in two individuals with hearing loss. It has … (more) The p.Ser105Tyr variant in SERPINB6 has been previously reported by our laborato ry in the heterozygous state in two individuals with hearing loss. It has also been identified in 0.1% (102/126684) of European chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148530934). A lthough this variant has been seen in the general population, its frequency is n ot high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ser105Tyr variant i s uncertain. (less) Number of individuals with the variant: 3

Comment:

This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 105 of the SERPINB6 protein (p.Ser105Tyr). This variant is present in population databases (rs148530934, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SERPINB6-related conditions. ClinVar contains an entry for this variant (Variation ID: 229240). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

Comment:

The c.314C>A (p.S105Y) alteration is located in exon 4 (coding exon 3) of the SERPINB6 gene. This alteration results from a C to A substitution at nucleotide position 314, causing the serine (S) at amino acid position 105 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

The p.Ser105Tyr variant in SERPINB6 has been previously reported by our laborato ry in the heterozygous state in two individuals with hearing loss. It has also been identified in 0.1% (102/126684) of European chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148530934). A lthough this variant has been seen in the general population, its frequency is n ot high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ser105Tyr variant i s uncertain.

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:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs148530934 ...

These 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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_004568.6(SERPINB6):c.314C>A (p.Ser105Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs148530934 ...