VCV000044232.62 - ClinVar

NM_001289808.2(CRYAB):c.152C>T (p.Pro51Leu)

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.

(17)

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(2); Benign(3); Likely benign(6)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001289808.2(CRYAB):c.152C>T (p.Pro51Leu)

Variation ID: 44232 Accession: VCV000044232.62

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.1 11: 111911573 (GRCh38) [ NCBI UCSC ] 11: 111782297 (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	Dec 6, 2016	Oct 20, 2024	Jan 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001289808.2:c.152C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001276737.1:p.Pro51Leu	missense
NM_001289807.1:c.152C>T	NP_001276736.1:p.Pro51Leu	missense
NM_001368245.1:c.152C>T	NP_001355174.1:p.Pro51Leu	missense
NM_001885.3:c.152C>T	NP_001876.1:p.Pro51Leu	missense
NC_000011.10:g.111911573G>A
NC_000011.9:g.111782297G>A
NG_009824.3:g.17150C>T
NG_033080.2:g.3838G>A
LRG_407:g.17150C>T
LRG_407t1:c.152C>T	LRG_407p1:p.Pro51Leu
LRG_407t2:c.152C>T	LRG_407p2:p.Pro51Leu
	P02511:p.Pro51Leu

... more HGVS ... less HGVS

Protein change

P51L

Other names

p.P51L:CCA>CTA

Canonical SPDI

NC_000011.10:111911572:G:A

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.

0.00040 (A)

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

Exome Aggregation Consortium (ExAC) 0.00045

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

The Genome Aggregation Database (gnomAD), exomes 0.00057

Trans-Omics for Precision Medicine (TOPMed) 0.00064

The Genome Aggregation Database (gnomAD) 0.00068

Links

UniProtKB: P02511#VAR_014608 dbSNP: rs2234704 ClinGen: CA133792 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.
CRYAB		-	-	GRCh38 GRCh37	276	312

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	Likely benign (4)	criteria provided, multiple submitters, no conflicts	Feb 6, 2018	RCV000037211.21
Fatal infantile hypertonic myofibrillar myopathy	Uncertain significance (1)	criteria provided, single submitter	Jan 12, 2018	RCV000280721.13
Myofibrillar myopathy 2	Benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV000320693.13
Cataract 16 multiple types	Benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV000375343.13
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Dec 5, 2018	RCV000620871.11
not provided	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Jun 1, 2023	RCV000726131.42
Cardiomyopathy	Benign (1)	criteria provided, single submitter	Oct 16, 2018	RCV000769291.11
Dilated cardiomyopathy 1II	Likely benign (1)	criteria provided, single submitter	Jan 26, 2024	RCV001082909.16
CRYAB-related disorder	Likely benign (1)	no assertion criteria provided	Dec 6, 2019	RCV003924915.2

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 (Feb 06, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000235759.12 First in ClinVar: Jul 05, 2015 Last updated: Apr 09, 2018	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (Apr 20, 2016)	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: SCV000060868.5 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Publications: PubMed (1) PubMed: 11013455 Comment: p.Pro51Leu in exon 1 of CRYAB: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including … (more) p.Pro51Leu in exon 1 of CRYAB: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, mouse lemur, tree shrew, dolphin, and armadillo have a leucine (Leu, this va riant) at this position despite high nearby amino acid conservation. In addition , computational analyses (AlignGVGD, PolyPhen2, SIFT) do not suggest a high like lihood of impact to the protein. Additionally, the Pro51Leu variant has been ide ntified in 44/57370 European chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP rs2234704). (less) Number of individuals with the variant: 4
Likely benign (Feb 16, 2020)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001473708.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Uncertain significance (Jun 08, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000342239.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CRYAB Number of individuals with the variant: 1 Sex: mixed
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Myofibrillar myopathy 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000367271.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Cataract 16 multiple types Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000367272.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Uncertain significance (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Fatal infantile hypertonic myofibrillar myopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000367273.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Benign (Oct 16, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV000900669.2 First in ClinVar: May 06, 2019 Last updated: May 31, 2020
Likely benign (Jan 26, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Dilated cardiomyopathy 1II Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000563212.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024
Likely benign (Dec 05, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000736950.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 11013455‚ 26265630 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Jun 01, 2023)	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: SCV001148457.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: CRYAB: BP4 Number of individuals with the variant: 2
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001742113.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001918529.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001970470.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely benign (Dec 06, 2019)	no assertion criteria provided Method: clinical testing	CRYAB-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004738169.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930754.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953235.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

p.Pro51Leu in exon 1 of CRYAB: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, mouse lemur, tree shrew, dolphin, and armadillo have a leucine (Leu, this va riant) at this position despite high nearby amino acid conservation. In addition , computational analyses (AlignGVGD, PolyPhen2, SIFT) do not suggest a high like lihood of impact to the protein. Additionally, the Pro51Leu variant has been ide ntified in 44/57370 European chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP rs2234704).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A Rapid, High-Quality, Cost-Effective, Comprehensive and Expandable Targeted Next-Generation Sequencing Assay for Inherited Heart Diseases.	Wilson KD	Circulation research	2015	PMID: 26265630
Five novel genetic variants in the promoter and coding region of the alpha B-crystallin gene (CRYAB): -652G>A, -650C>G, -249G>C, S41Y, P51L.	Hahner A	Human mutation	2000	PMID: 11013455
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CRYAB	-	-	-	-

Text-mined citations for rs2234704 ...

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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_001289808.2(CRYAB):c.152C>T (p.Pro51Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2234704 ...