VCV001678710.9 - ClinVar

NM_004568.6(SERPINB6):c.1096G>A (p.Gly366Arg)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance
Uncertain significance (4)

4 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004568.6(SERPINB6):c.1096G>A (p.Gly366Arg)

Variation ID: 1678710 Accession: VCV001678710.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p25.2 6: 2948333 (GRCh38) [ NCBI UCSC ] 6: 2948567 (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 29, 2022	Aug 30, 2025	Aug 22, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_004568.6:c.1096G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004559.4:p.Gly366Arg	missense
NM_001195291.3:c.1108G>A	NP_001182220.2:p.Gly370Arg	missense
NM_001271822.2:c.1138G>A	NP_001258751.1:p.Gly380Arg	missense
NM_001271823.2:c.1153G>A	NP_001258752.1:p.Gly385Arg	missense
NM_001271824.2:c.1096G>A	NP_001258753.1:p.Gly366Arg	missense
NM_001271825.2:c.1096G>A	NP_001258754.1:p.Gly366Arg	missense
NM_001297699.2:c.1096G>A	NP_001284628.1:p.Gly366Arg	missense
NM_001297700.2:c.1096G>A	NP_001284629.1:p.Gly366Arg	missense
NM_001374515.1:c.1108G>A	NP_001361444.1:p.Gly370Arg	missense
NM_001374516.1:c.1096G>A	NP_001361445.1:p.Gly366Arg	missense
NM_001374517.1:c.964G>A	NP_001361446.1:p.Gly322Arg	missense
NR_164657.1:n.1145G>A		non-coding transcript variant
NC_000006.12:g.2948333C>T
NC_000006.11:g.2948567C>T
NG_027692.1:g.28833G>A

... more HGVS ... less HGVS

Protein change

G322R, G366R, G370R, G380R, G385R

Other names

Canonical SPDI

NC_000006.12:2948332:C:T

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.

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

The Genome Aggregation Database (gnomAD) 0.00006

The Genome Aggregation Database (gnomAD) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00005

Links

ClinGen: CA3617353 dbSNP: rs765798757 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		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	217	276

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 provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 22, 2025	RCV002226024.7
Autosomal recessive nonsyndromic hearing loss 91	Uncertain significance (1)	criteria provided, single submitter	Jul 8, 2021	RCV002487029.1
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 22, 2024	RCV004673649.1

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.	Expand all rows Collapse all rows 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.
Uncertain significance (Jul 08, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Autosomal recessive nonsyndromic hearing loss 91	Fulgent Genetics, Fulgent Genetics Accession: SCV002781166.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (Apr 22, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	not specified	Ambry Genetics Accession: SCV005160007.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Comment: show The c.1096G>A (p.G366R) alteration is located in exon 7 (coding exon 6) of the SERPINB6 gene. This alteration results from a G to A substitution at nucleotide position 1096, causing the glycine (G) at amino acid position 366 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jun 02, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003250660.3 First in ClinVar: Feb 07, 2023 Last updated: Feb 25, 2025	Comment: show This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 366 of the SERPINB6 protein (p.Gly366Arg). This variant is present in population databases (rs765798757, gnomAD 0.01%). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1678710). This variant has not been reported in the literature in individuals affected with SERPINB6-related conditions. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Aug 22, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV002504005.3 First in ClinVar: Apr 29, 2022 Last updated: Aug 30, 2025	Comment: show In silico analysis suggests that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

The c.1096G>A (p.G366R) alteration is located in exon 7 (coding exon 6) of the SERPINB6 gene. This alteration results from a G to A substitution at nucleotide position 1096, causing the glycine (G) at amino acid position 366 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 366 of the SERPINB6 protein (p.Gly366Arg). This variant is present in population databases (rs765798757, gnomAD 0.01%). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1678710). This variant has not been reported in the literature in individuals affected with SERPINB6-related conditions.

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 rs765798757 ...

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 Aug 30, 2025